Liau 

et al. J Transl Med (2018) 16:142

https://doi.org/10.1186/s12967-018-1507-6 Journal of
Translational Medicine

RESEARCH Open Access

First results on survival from a large Phase

3 clinical trial of an autologous dendritic cell
vaccine in newly diagnosed glioblastoma
Linda M. Liau1*, Keyoumars Ashkan2, David D. Tran3, Jian L. Campian4, John E. Trusheim5, Charles S. Cobbs6,
Jason A. Heth7, Michael Salacz8, Sarah Taylor8, Stacy D. D’Andre9, Fabio M. Iwamoto10, Edward J. Dropcho11,
Yaron A. Moshel12, Kevin A. Walter13, Clement P. Pillainayagam14, Robert Aiken15, Rekha Chaudhary16,
Samuel A. Goldlust17, Daniela A. Bota18, Paul Duic19, Jai Grewal59, Heinrich Elinzano20, Steven A. Toms20,
Kevin O. Lillehei21, Tom Mikkelsen22, Tobias Walpert22, Steven R. Abram23, Andrew J. Brenner24,
Steven Brem25, Matthew G. Ewend26, Simon Khagi26, Jana Portnow27, Lyndon J. Kim28, William G. Loudon29,
Reid C. Thompson30, David E. Avigan31, Karen L. Fink32, Francois J. Geoffroy33, Scott Lindhorst34,
Jose Lutzky35, Andrew E. Sloan36, Gabriele Schackert37, Dietmar Krex37, Hans‑Jorg Meisel38, Julian Wu39,
Raphael P. Davis40, Christopher Duma41, Arnold B. Etame42, David Mathieu43, Santosh Kesari44, David Piccioni44,
Manfred Westphal45, David S. Baskin46, Pamela Z. New46, Michel Lacroix47, Sven‑Axel May48, Timothy J. Pluard49,
Victor Tse50, Richard M. Green51, John L. Villano52, Michael Pearlman53, Kevin Petrecca54, Michael Schulder55,
Lynne P. Taylor56, Anthony E. Maida58, Robert M. Prins1, Timothy F. Cloughesy1, Paul Mulholland57
and Marnix L. Bosch58* 

Abstract 

evaluates the addition of an autologous tumor lysate-pulsed dendritic cell vaccine ­(DCVax®-L) to standard therapy for
Background:  Standard therapy for glioblastoma includes surgery, radiotherapy, and temozolomide. This Phase 3 trial

newly diagnosed glioblastoma.

Methods:  After surgery and chemoradiotherapy, patients were randomized (2:1) to receive temozolomide plus
DCVax-L (n = 232) or temozolomide and placebo (n = 99). Following recurrence, all patients were allowed to receive
DCVax-L, without unblinding. The primary endpoint was progression free survival (PFS); the secondary endpoint was
overall survival (OS).
Results:  For the intent-to-treat (ITT) population (n = 331), median OS (mOS) was 23.1 months from surgery. Because
of the cross-over trial design, nearly 90% of the ITT population received DCVax-L. For patients with methylated
MGMT (n = 131), mOS was 34.7 months from surgery, with a 3-year survival of 46.4%. As of this analysis, 223 patients
are ≥ 30 months past their surgery date; 67 of these (30.0%) have lived ≥ 30 months and have a Kaplan-Meier (KM)-
derived mOS of 46.5 months. 182 patients are ≥ 36 months past surgery; 44 of these (24.2%) have lived ≥ 36 months
and have a KM-derived mOS of 88.2 months. A population of extended survivors (n = 100) with mOS of 40.5 months,
not explained by known prognostic factors, will be analyzed further. Only 2.1% of ITT patients (n = 7) had a grade 3

*Correspondence: lliau@mednet.ucla.edu; marnix@nwbio.com

1
University of California Los Angeles (UCLA) David Geffen School
of Medicine & Jonsson Comprehensive Cancer Center, Los Angeles, CA,
USA
58
Northwest Biotherapeutics Inc., Bethesda, MD, USA
Full list of author information is available at the end of the article

© The Author(s) 2018. This article is distributed under the terms of the Creative Commons Attribution 4.0 International License
(http://creat​iveco​mmons​.org/licen​ses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium,
provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license,
and indicate if changes were made. The Creative Commons Public Domain Dedication waiver (http://creat​iveco​mmons​.org/
publi​cdoma​in/zero/1.0/) applies to the data made available in this article, unless otherwise stated.
Liau et al. J Transl Med (2018) 16:142
or 4 adverse event that was deemed at least possibly related to the vaccine. Overall adverse events with DCVax were
comparable to standard therapy alone.
Conclusions:  Addition of DCVax-L to standard therapy is feasible and safe in glioblastoma patients, and may extend
survival.
Trial registration Funded by Northwest Biotherapeutics; Clinicaltrials.gov number: NCT00045968; https​://clini​caltr​ials.
gov/ct2/show/NCT00​04596​8?term=NCT00​04596​8&rank=1; initially registered 19 September 2002
Keywords:  Glioblastoma, Immunotherapy, Dendritic cell, Vaccine
Background
Glioblastoma is the most aggressive primary malig-
nant brain tumor in adults [1]. Standard of care (SOC)
consists of surgical resection followed by 6  weeks of
daily radiotherapy with concurrent temozolomide, then
monthly temozolomide [2]. Median overall survival
(mOS) under this SOC is only 15–17  months [2, 3],
and ≤ 5% of patients are alive at 5 years [3]. Loco-regional
therapy with alternating electric fields has recently shown
an increase in median PFS (mPFS) to 6.7  months and
mOS to 20.9  months from randomization, respectively
[4]. However, there has been no material advance in sur-
vival with systemic therapies since the addition of temo-
zolomide 12 years ago, despite investigations with many
diverse agents [2, 5–10].
Immunotherapy is an appealing strategy because of the
potential ability for immune cells to traffic to and destroy
infiltrating tumor cells. Dendritic cells (DCs) are central
to the immune system as key regulators of immune tol-
erance and immunity [11]. For more than a decade, our
group and others have been testing active vaccination
strategies, such as DCs pulsed with tumor lysates or syn-
thetic peptides to induce antitumor immunity in glioblas-
toma patients [12, 13]. We have previously demonstrated
the effectiveness of DC vaccination in pre-clinical models
[14–16], and early stage clinical trials have shown sub-
stantial promise [17–19].
In this report, we describe the blinded interim data of
the overall ITT patient population enrolled in a Phase 3
randomized, double-blinded, placebo-controlled clini-
cell vaccine (­DCVax®-L) for newly diagnosed glio-
cal trial of an autologous tumor lysate-pulsed dendritic
blastoma. To date, we have not yet reached sufficient
events (i.e., deaths) in this trial to justify unblinding.
Nevertheless, since the vast majority (86.4%) of the ITT
population received the experimental DC treatment at
some point during the trial because of the cross-over
study design, analysis of the interim data may provide
early insight into the impact of DCVax-L on overall
survival. A final analysis of the data obtained in this
trial following unblinding will occur once sufficient
events of disease progression or death have occurred
Page 2 of 9
to fully elucidate patient survival data in the tail of the
survival curve.
Methods
Study patients
Patients were eligible for this study if they were
18–70  years of age and had newly diagnosed glioblas-
toma, as determined through central pathology review.
Other eligibility criteria included Karnofsky Perfor-
mance Score (KPS) of ≥ 70 [20], adequate bone marrow,
liver, and renal function, life expectancy of ≥ 8  weeks,
no other prior malignancy within the last 5  years, no
active viral infections, and sufficient resected tumor
material to produce the autologous vaccine. Patients
were excluded if they already had apparent early dis-
ease progression/recurrence or pseudo-progression at
the baseline visit, similar to the inclusion/exclusion cri-
teria of other recent trials in glioblastoma [4, 21].
Study design and treatments
We conducted this study at over 80 sites in 4 countries:
the US, Canada, Germany, and the UK. Patient recruit-
ment was initiated in 2007, and was paused from 2009
to 2011 for economic reasons. The midpoint of enroll-
ment was reached in May of 2014, and the final patient
was enrolled in November of 2015. The protocol was
approved by the required independent ethics commit-
tees and institutional review boards. Written consent was
obtained from all patients participating in the trial.
All patients underwent surgical resection and 6 weeks
of chemoradiotherapy per SOC, prior to enrollment and
randomization in the study.
Randomization was performed centrally and was strati-
fied by clinical site and MGMT ­(O6-methylguanine-DNA
methyltransferase) gene promoter methylation status,
which was determined by a central laboratory. Patients
were randomized 2:1 to SOC plus autologous DC vac-
cine (DCVax-L; n = 232) or SOC plus placebo (n = 99).
PBMCs were used as placebo control as these cells are
visually indistinguishable from DC and are consid-
ered immunologically inactive. Patients in both arms
Liau et al. J Transl Med (2018) 16:142
continued to receive monthly adjuvant temozolomide
(150–200  mg/m2/day ×  5  days every 28  days), inter-
spersed with the DC vaccine or placebo treatments
administered on Days 0, 10 and 20, then Months 2, 4 and
8, and thereafter at 6-month intervals starting at month
12. Each DCVax-L treatment involved a dose of 2.5 mil-
lion autologous tumor lysate-pulsed DCs administered
intradermally in the upper arm, alternating arms between
injection visits.
All patients were allowed to receive DCVax-L following
tumor progression/recurrence, as well as other approved
treatments per local practice. All parties (investigators,
patients and sponsor) remained blinded as to which
treatment each patient had received prior to crossover.
All patients who chose this option were given the active
treatment on a re-start schedule with immunizations at
Days 0, 10 and 20, and then months 2, 4 and 8, and every
6 months thereafter beginning with month 12, with Day 0
being the day of the first vaccination post progression. To
date, DCVax-L has been shipped for 286 patients (86.4%)
in the trial.
Both the study treatment (DCVax-L) and placebo
(PBMC) were prepared by Cognate BioServices, Inc. for
all patients in the US and Canada, and by Cognate and
the Fraunhofer Institute for Cell Therapy together for
patients in Europe, during the chemoradiotherapy period
before the baseline visit. The production of DCVax-
L involved processing the resected tumor tissue into a
lysate, and then collection, purification, differentiation,
activation and loading of the autologous DCs. In general,
approximately 2 g of tumor tissue was needed to produce
the full ten doses for the 36-month treatment and follow-
up schedule. The vaccine was aliquoted in individual
doses and cryopreserved at < 150 °C [22]. The doses were
stored centrally, and shipped individually to the clinical
trial sites.
Assessments
Baseline assessments included physical examination, neu-
rological examination, vitals, KPS, MRI of brain with and
without contrast, hematology (CBC with differential, plate-
lets), and serum chemistries (calcium, magnesium, SGOT,
SGPT, alkaline phosphatase, LDH, total bilirubin, BUN,
creatinine, electrolytes, glucose). Blood was collected for
serum markers of autoimmune disease (anti-DNA) and
immune monitoring, at the baseline visit and at treatment
visits throughout the trial. MRI brain scans were performed
every 2 months, per SOC, after the baseline MRI until radi-
ological tumor progression. All MRI scans were evaluated
centrally by 2 blinded independent radiologists, with adju-
dication by a third such radiologist if needed.
Adverse events were recorded prospectively according
to the National Cancer Institute’s Common Terminology
Page 3 of 9
Criteria (version 3.0 NCI CTC), until 2 months after the
last study treatment. Patients are followed for OS until
death.
Statistical analyses
The study’s primary endpoint is  PFS, and the secondary
endpoint is OS. PFS has not yet been evaluated for this
publication and will be the subject of later analyses to
allow for central, multi-factorial assessment by an expert
panel, using criteria currently emerging as appropriate
for immune therapy in this patient population where pro-
gression can be complex to determine and pseudo-pro-
gression is a known confounding phenomenon. Analysis
of the blinded interim data on OS of the ITT population
(using SAS version 9.4) was performed 34  months after
the midpoint of patient enrollment, and 16 months after
the last patient was enrolled and randomized.
General descriptive statistics include the number of
observed values, mean, standard deviation, median, and
range values for continuous measures. For categorical
variables, the number and percentage of subjects with
a specific level of the variable are reported. For survival
analyses, Kaplan–Meier (KM) curves were generated,
yielding estimates of median survival times, along with
the two-sided confidence intervals (95% CIs) and esti-
mates of survival at specific time points.
Results
Study patients
From July 2007 to November 2015, 331 patients were
recruited in the trial, comprising the intent-to-treat
(ITT) population. A flow diagram depicting the flow of
patients through the screening and enrollment process is
provided in Fig. 1. The median time from surgery to ran-
domization was 3.1 months.
The ITT population (n = 331) (Table  1) is similar to
other recent glioblastoma trials [4, 21, 24], with 61% males
(n = 202) and 39% females (n = 129), with 75.2% of the
patients ≥ 50 years of age (range 19–73 years), and median
KPS of 90. 63.1% of patients (n = 209) had gross total
resection and 36.9% (n = 122) did not. The MGMT gene
promoter was methylated in 39.6% of patients (n = 131)
and unmethylated in 48.9% (n = 162), with information not
available for 11.5% (n = 38; the missing data relates to the
early patients enrolled a decade ago). Absolute lymphocyte
count (ALC) was > 800 cells/mm3 in 48.6% of the patients
(n = 161) and was < 800  cells/mm3 in 51.4% of patients
(n = 170), a characteristic that has been associated with
poor prognosis after radiation [23]. Patients with radio-
graphic evidence of disease progression at baseline were
excluded, as they have also been excluded in other recent
trials for newly diagnosed glioblastoma [4, 21, 24].
Liau et al. J Transl Med (2018) 16:142 Page 4 of 9

Table 1  Baseline demographic and clinical characteristics

Variable n = 331 (100%)

Age (year)
 Mean (SD) 55.33 (10.01)
 Median (range) 56 (19, 73)
Sex, n (%)
 Female 129 (39.0)
 Male 202 (61.0)
Race, n (%)
 American Indian or Alaska Native 1 (0.3)
 Asian 2 (0.6)
 Black or African American 7 (2.1)
 Hispanic or Latino 16 (4.8)
 White 294 (88.8)
 Not ­availablea 11 (3.3)
KPS at baseline, n (%)
 < 90 97 (29.3)
 ≥ 90 234 (70.7)
MGMT classification, n (%)
Fig. 1  Recruitment, inclusion, and randomization of patients in the
study. (1) Patients are screened prior to surgery, so glioblastoma  Methylated 131 (39.6)
(GBM) determination is made from pathological diagnosis  Not methylated 162 (48.9)
after surgery. (2) Insufficient tumor lysate generated to meet  Not available 38 (11.5)
threshold. (3) Progressive disease or pseudo-progression (which
Lymphocyte group, n (%)
are indistinguishable at this point) based on central review of MRI
imaging at baseline post-chemoradiation. (4) Patients who consented  High 161 (48.6)
to tumor donation but then declined participation in trial prior to  Low 170 (51.4)
leukapheresis. (5) Includes deviations from standard chemoradiation Surgical status, n (%)
protocol, history of prior malignancy, inadequate renal or bone  Partial resection 122 (36.9)
marrow function, etc. (6) Includes drug product failure or insufficient
 Complete resection 209 (63.1)
drug or placebo manufactured to meet release criteria. (7) Includes
a
clinical deterioration, declining Karnofsky performance status, or   Race is in some cases not collected due to institutional policy
patient deaths. (8) Includes biopsy only, surgery canceled, or tumor
tissue not processed after surgery
Long tail among ITT population
With immune-based therapies, a key focus is on the tail
Since other treatments were allowed following disease of the survival curve [26]. Among the ITT patients with
progression, we assessed their usage in this trial. While a surgery date ≥ 30 months prior to the data collection (n
on study, three patients (1%) had another resection, 103 = 223), 30% (n = 67) have lived ≥ 30  months, and their
patients (31%) received bevacizumab, 53 patients (16%) KM-derived mOS estimate is 46.5  months. Among the
received CCNU and 6 patients (1.8%) were treated with ITT patients with a surgery date ≥ 36  months prior to
tumor treating fields. In multiple reported studies, nei- the data collection (n = 182), 24.2% (n = 44) have lived
ther bevacizumab nor CCNU have been shown to extend ≥ 36  months and their KM-derived mOS estimate is
survival [9, 25]. 88.2 months.

Treatment outcomes MGMT status and extent of resection

ITT population
At the time of this analysis, 108 the 331 patients (32.6%)
were still alive. The mOS of the overall ITT population
(n = 331) was 23.1 months from the time of surgery (95%
CI 21.2–25.4), with 2 and 3-year survival rates of 46.2
and 25.4%, respectively (see Fig. 2a and Table 2). Analy-
sis of patient survival relative to year of enrollment did
not reveal a trend over time, nor meaningful differences
between years.
In patients with methylated MGMT (n = 131), mOS was
34.7 months from surgery (95% CI 27.0–40.7), with 2 and
3-year survival rates of 66.7% and 46.4%, respectively. In
patients with unmethylated MGMT (n = 162), mOS was
19.8 months from surgery (95% CI 17.9–21.7), with 2 and
3-year survival rates of 32.1%, and 11.0%, respectively
(Fig. 2b and Table 2).
For patients with gross total surgical resection
(n = 209), mOS was 25.4  months from surgery (95% CI
Liau et al. J Transl Med (2018) 16:142 Page 5 of 9

Fig. 2  Overall survival curves for patients in the intent-to-treat population. Overall survival analyses of time from date of surgery until death or
last follow-up according to the Kaplan–Meier method for all patients in the intent-to-treat (ITT) population (a), and the ITT population stratified by
MGMT gene promoter methylation status (b). Censored patients are annotated by a small vertical line

21.8–28.2), with 2 and 3-year survival rates of 51.2%, and
29.9%, respectively. For patients with only partial surgical
resection (n = 122), mOS from surgery was 21.1 months
(95% CI 19.1–23.1), with 2 and 3-year survival rates of
37.7%, and 18.0%, respectively (Table 2).
In patients with both MGMT methylation and gross
total resection (n = 83), the mOS was 36.5 months (95%
CI 31.5–46.5)—1.8  months longer than the mOS of
patients with MGMT methylation and only partial resec-
tion (n = 48). In patients with unmethylated MGMT,
Liau et al. J Transl Med (2018) 16:142 Page 6 of 9

Table 2  Study endpoints according to molecular genetic and clinical prognostic subgroups

Population n Median OS Survival at 1 yearb Survival at 2 yearsb Survival at 3 yearsb
since surgery (months)a

Overall 331 23.1 89.3% 46.2% 25.4%

(21.2, 25.4) (85.4, 92.2) (40.4, 51.8) (19.9, 31.3)
MGMT methylated 131 34.7 94.5% 66.7% 46.4%
(27.0, 40.7) (88.8, 97.3) (57.5, 74.4) (35.8, 56.3)
MGMT un-methylated 162 19.8 86.4% 32.1% 11.0%
(17.9, 21.7) (80.0, 90.8) (24.5, 9.9) (5.7, 18.2)
Gross total resection 209 25.4 91.8% 51.2% 29.9%
(21.8, 28.2) (87.1, 94.8) (43.9, 58.1) (22.6, 37.5)
Partial resection 122 21.1 85.0% 37.7% 18.0%
(19.1, 23.1) (77.2, 90.2) (28.6, 46.7) (10.5, 27.1)
KPS at baseline ≥ 90 234 23.7 94.0% 49.2% 26.6%
(21.8, 26.7) (90.0, 96.4) (42.3, 55.8) (19.9, 33.8)
KPS at baseline < 90 97 19.8 77.8% 38.8% 22.1%
(16.6, 23.9) (68.0, 84.9) (28.5, 49.0) (13.4, 32.2)
ALC > 800 161 23.6 89.9% 49.5% 28.7%
(21.7, 28.2) (84.0, 93.7) (41.1, 57.4) (20.6, 37.3)
ALC ≤ 800 170 21.6 88.7% 43.3% 22.2%
(19.9, 25.2) (82.8, 92.6) (35.4, 50.9) (15.0, 30.3)
Age < 50 years 82 26.2 92.5% 51.7% 28.0%
(21.1, 31.5) (84.2, 96.6) (39.9, 62.3) (16.4, 40.8)
Age ≥ 50 years 249 22.4 88.2% 44.4% 24.6%
(20.4, 24.1) (83.5, 91.7) (37.7, 50.8) (18.5, 31.2)
a
  Median overall survival (OS) in months of intent-to-treat (ITT) population, followed by 95% confidence interval in parentheses
b
  Annual rates of percentage surviving in ITT population, followed by 95% confidence interval in parentheses

there was no statistically significant survival advan-
tage with gross total resection compared to only partial
resection.
Unknown factors: sub‑group with extended survival
Approximately 30% of the ITT population (n  = 100)
showed particularly extended survival, with a KM
derived mOS estimate of 40.5  months. This is not fully
explained by known prognostic factors, as only some of
these patients had positive prognostic factors: only 29%
were younger than 50 years of age, 65.9% had methylated
MGMT, 71% had a complete resection, and only 8% of
these patients had all three positive prognostic factors.
These patients will be the subject of extensive further
analyses and research.
Safety and toxicity
Safety and toxicity data were assessed on a blinded basis
for all 331 ITT patients. Following SOC chemoradio-
therapy, and before any DCVax-L treatment, lymphope-
nia was the most common adverse event, occurring in
approximately 170 patients (51%) [23].
The DCVax-L treatment was well tolerated, with only
7 ITT patients (2.1%) experiencing serious (NCI CTC
Grades 3–4) adverse events that were deemed related
or possibly related to the DCVax-L treatment. These
included cerebral edema in 3 patients (0.9%), seizures in
2 patients (0.6%), nausea in 1 patient (0.3%) and lymph
gland infection in 1 patient (0.3%).
The rate of total adverse events with SOC plus DCVax-
L was comparable to SOC alone (Table  3). Non-serious
adverse events that were considered possibly related to
the treatment included injection site reactions, fatigue,
low-grade fever and night chills.
Discussion
Although enrollment was completed in 2015, this trial,
including both treatments and follow-up, is still ongoing
and will remain blinded until sufficient events of disease
progression and/or death have occurred to more fully
elucidate the tail of the survival curve. To date, due to
the crossover design, nearly 90% of the ITT population
received DCVax-L at some point in the trial, due to the
crossover design.
DCVax-L is administered by intra-dermal injection in
the arm, six times in year one and twice per year there-
after. It thereby imposes only a minimal burden on the
patient.
In the overall ITT population in this trial, the mOS of
23.1  months from surgery compares favorably with the
mOS of 15–17  months from surgery typically achieved
Liau et al. J Transl Med (2018) 16:142 Page 7 of 9

Table 3 Grades 3–4 treatment-emergent adverse events in trial designs a decade ago when this trial began. It will
(TEAE) be collected and analyzed later, but is unlikely to explain
System organ c­ lassa Number (%) the overall survival results, as the mutation associated
of patients with TEAE with prolonged survival occurs in less than 10% of newly
(n = 331) diagnosed glioblastoma patients [27].
Patients reporting at least one serious TEAE 137 (41.1%) Beneficial effects of immune therapies are often
(whether or not related to DC vaccine treat‑ observed at later time points, in the tail of the survival
ment) curve [26]. Although this Phase 3 trial requires fur-
Nervous system disorders 93 (28.1%) ther maturation, a picture is beginning to emerge from
Infectionsb 23 (6.9%) the blinded interim data which is consistent with an
General disorders and injection site reactions 22 (6.6%) extended survival tail. For example, among the patients
Respiratory, thoracic and mediastinal disorders 17 (5.1%) (n = 182) who were ≥ 36  months past their surgery date
Psychiatric disorders 16 (4.8%) as of the date of this analysis, 24.2% (n = 44) were alive
Gastrointestinal disorders 16 (4.8%) for ≥ 36  months and have a KM estimated median sur-
Injury, poisoning, and procedural complications 12 (3.6%) vival time of 88.2 months. Thus, it appears that patients
Vascular disorders 6 (1.8%) who survive past certain threshold time points may con-
Musculoskeletal and connective tissue disor‑ 5 (1.5%) tinue onwards to unusually long survival times, similar
ders
to the findings in our prior Phase I/II studies of this DC-
Neoplasms benign, malignant and unspecified 5 (1.5%)
based vaccine [17–19]. Further maturation of the trial
Hematological disorders 5 (1.5%)
data is needed to more fully reveal the extent of the long
Metabolism and nutrition disorders 3 (0.9%)
tail of the survival curve.
Hepatobiliary disorders 2 (0.6%)
DCVax-L has shown a benign safety profile in this
Renal and urinary disorders 2 (0.6%)
Phase 3 study, as it has consistently done in prior early
Cardiac disorders 1 (0.3%)
stage trials [17, 19], and in a large group of patients
Ear and labyrinth disorders 1 (0.3%) treated on a compassionate use basis [28]. The fact that
Immune system ­disordersc 1 (0.3%) only 7 of the 331 ITT patients (2.1%) experienced any
Reproductive system and breast disorders 1 (0.3%) grade 3 or 4 adverse events that were at least possibly
a
  Coded per MedDRA 16.0. Patients may have had more than one adverse event, related to the treatment makes this DC vaccine an espe-
so subcategories do not total
b
cially well tolerated treatment.
  Includes surgical wound infections, meningitis, urinary tract infections, and
others With such a safety profile, this DC vaccine may be
c
  Includes drug hypersensitivity administered in a wide range of clinical settings, and
can potentially be combined with a wide range of other
with SOC in past studies and clinical practice, as well as treatment agents, including immune checkpoint inhibi-
with the survival data with SOC treatment in the control tors and targeted therapies, without resulting in undue
arms of other trials in similar patient populations. For toxicities for patients such as have been seen with some
example, Weller et al. reported mOS of 17.4 months from other treatment combinations [29, 30]. Further studies to
randomization in the ITT population [21], and Stupp explore such combinations are warranted.
et al. reported mOS of 16.0 months from randomization
in the ITT population [24]. Conclusions
In patients with a methylated MGMT gene promoter, The addition of DCVax-L autologous dendritic cell vac-
the mOS of 34.7  months from surgery also compares cine to SOC is feasible and safe. Collectively, the blinded
favorably with SOC in past studies as well as with the interim survival data suggest that the patients in this
mOS reported for the control arm SOC treatments in Phase 3 trial are living longer than expected. These find-
other recent glioblastoma trials in similar patient popu- ings warrant further follow up and analyses.
lations. For example, Stupp et al. reported for their con-
trol group an  mOS of 21.2  months from randomization Authors’ contributions
LL and MB conceived of and designed the study. LL, KA, DDT, JLC, TET, CSC,
in a similar patient population [24]. The increase in JAH, MS, ST, SDD, FMI, EJD, YAM, KAW, CPP, RA, RC, SAG, DAB, PD, JG, HE, SAT,
survival in MGMT-methylated patients in the DCVax- KOL, TM, TW, SRA, AJB, SB, MGE, AK, JP, LJK, WGL, RCT, DEA, KLF, FJG, SL, JL, AES,
L trial raises the possibility of a cooperative effect from GS, DK, H-JM, JW, RPD, CD, ABE, DM, SK, DP, MW, DSB, PZN, ML, S-AM, TJP, VT,
RMG, JLV, MP, KP, MS, LPT, and PM contributed to collection of the data. EB
the combination of temozolomide chemotherapy and the served as the consulting statistician. All authors were involved in critical review
DCVax-L active immune therapy [17]. of the data, or drafting, reviewing or revising the manuscript or approving
The mutation status of the IDH1 gene has not yet been the final version. LL enrolled the greatest number of patients in the USA and
KA enrolled the greatest number of patients in the EU. All authors read and
investigated for this trial, as this factor was not included approved the final manuscript.
Liau et al. J Transl Med (2018) 16:142
Author details
1
 University of California Los Angeles (UCLA) David Geffen School of Medicine
& Jonsson Comprehensive Cancer Center, Los Angeles, CA, USA. 2 King’s Col‑
lege London School of Medical Education, London, UK. 3 University of Florida,
Gainesville, FL, USA. 4 Washington University, St. Louis, MO, USA. 5 Abbott
Northwestern Hospital, Minneapolis, MN, USA. 6 Swedish Medical Center,
Swedish Neuroscience Institute, Seattle, WA, USA. 7 University of Michigan
Medical School, Ann Arbor, MI, USA. 8 University of Kansas Cancer Center, Kan‑
sas City, KS, USA. 9 Sutter Institute for Medical Research, Sacramento, CA, USA.
10
 Columbia University Medical Center, New York, NY, USA. 11 Indiana University
Simon Cancer Center, Indianapolis, IN, USA. 12 Overlook Medical Center, Sum‑
mit, NJ, USA. 13 University of Rochester Medical Center, Rochester, NY, USA.
14
 Rush University Medical Center, Rochester, USA. 15 Rutgers Cancer Institute,
New Brunswick, NJ, USA. 16 University of Cincinnati Medical Center, Cincinnati,
OH, USA. 17 Hackensack University Medical Center, Hackensack, NJ, USA. 18 UC
Irvine Medical Center, Irvine, CA, USA. 19 Winthrop-University Hospital, Mineola,
NY, USA. 20 Rhode Island Hospital, Providence, RI, USA. 21 University of Colo‑
rado Hospital, Aurora, CO, USA. 22 Henry Ford Health System, Detroit, MI, USA.
23
 St. Thomas Research Institute, Nashville, TN, USA. 24 University of Texas
Health Science Center, San Antonio, TX, USA. 25 University of Pennsylvania
Perelman School of Medicine, Philadelphia, PA, USA. 26 University of North
Carolina, Chapel Hill, NC, USA. 27 City of Hope National Medical Center, Duarte,
CA, USA. 28 Thomas Jefferson University, Philadelphia, PA, USA. 29 St. Joseph
Hospital, Newport Beach, CA, USA. 30 Vanderbilt University, Nashville, TN, USA.
31
 Beth Israel Deaconess Medical Center, Boston, MA, USA. 32 Baylor University
Medical Center, Dallas, TX, USA. 33 Illinois CancerCare, Peoria, IL, USA. 34 Medical
University of South Carolina, Charleston, SC, USA. 35 Mount Sinai Comprehen‑
sive Cancer Center, Miami, FL, USA. 36 University Hospitals Case Medical Center,
Cleveland, OH, USA. 37 University Hospital Carl-Gustav-Carus of Technical
University, Dresden, Germany. 38 BG-Klinikum Bergmannstrost, Halle, Germany.
39
 Tufts University School of Medicine, Boston, MA, USA. 40 Stony Brook Uni‑
versity, Stony Brook, NY, USA. 41 Hoag Cancer Center, Newport Beach, CA, USA.
42
 H. Lee Moffit Cancer Center and Research Institute, Tampa, FL, USA. 43 CHUS-
Hopital Fleurimont, Sherbrooke University, Sherbrooke, QC, Canada. 44 UCSD
Health System, UC San Diego, San Diego, CA, USA. 45 Neurochirurgische
Klinik University Clinic Hamburg-Eppendorf, Hamburg, Germany. 46 Houston
Methodist, Houston, TX, USA. 47 Geisinger Health System, Danville, PA, USA.
48
 Klinikum Chemnitz GGMBH, Chemnitz, Germany. 49 Saint Luke’s Cancer Insti‑
tute, Kansas City, MO, USA. 50 Kaiser Permanente Northern California, Redwood
City, CA, USA. 51 Kaiser Permanente Southern California, Los Angeles, CA, USA.
52
 University of Kentucky College of Medicine, Lexington, KY, USA. 53 Colorado
Neurological Institute, Englewood, CO, USA. 54 Montreal Neurological Institute
and Hospital, McGill University, Montreal, Canada. 55 Northwell Hofstra School
of Medicine, Lake Success, NY, USA. 56 Department of Neurology, Alvord Brain
Tumor Center, University of Washington, Seattle, WA, USA. 57 University College
Hospitals, London, UK. 58 Northwest Biotherapeutics Inc., Bethesda, MD, USA.
59
 NYU Winthrop Hospital, Mineola, NY, USA.
Acknowledgements
Supported by Northwest Biotherapeutics, Inc. and the UCLA SPORE in Brain
Cancer (P50-CA211015). We thank the patients who have participated in this
clinical trial and their families.
Competing interests
Dr. Bosch and Dr. Maida report being an employee of, holding stock or stock
options in, and receiving reimbursement for travel expenses from Northwest
Biotherapeutics, Inc.
Availability of data and materials
The datasets generated and/or analyzed during the current study are not
publicly available to protect future regulatory filings but access to the data
can be available through an independent statistician on a case by case basis,
as necessary and under confidentiality.
Consent for publication
Not applicable.
Ethics approval and consent to participate
The study was approved by Ethics Committees/Institutional Review boards at
all participating hospitals. Written consent was obtained from all patients prior
to participating in the study.
Page 8 of 9
Funding
Northwest Biotherapeutics, Inc. was the trial sponsor and had a role in the
design and conduct of the study, along with academic advisers; collection,
management, analysis, and interpretation of the data; preparation, review, and
approval of the manuscript; and decision to submit the manuscript for publi‑
cation. Data collected by the CRO from the investigators and their site person‑
nel were analyzed and interpreted on a blinded basis by senior academic
authors, independent statisticians, and representatives of the sponsor.
Publisher’s Note
Springer Nature remains neutral with regard to jurisdictional claims in pub‑
lished maps and institutional affiliations.
Received: 27 April 2018 Accepted: 7 May 2018
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